Colorectal adenocarcinoma-derived EGFR mutants are oncogenic and sensitive to EGFR-targeted monoclonal antibodies, cetuximab and panitumumab

Int J Cancer. 2020 Apr 15;146(8):2194-2200. doi: 10.1002/ijc.32499. Epub 2019 Jul 9.

Abstract

Somatic mutations of epidermal growth factor receptor (EGFR) occur in ~3% of colorectal cancer (CRC) patients. Here, through systematic functional screening of 21 recurrent EGFR mutations selected from public data sets, we show that 11 colon cancer-derived EGFR mutants (G63R, E114K, R165Q, R222C, S492R, P596L, K708R, E709K, G719S, G724S and L858R) are oncogenic and able to transform cells in a ligand-independent manner. We demonstrate that cellular transformation by these mutants requires receptor dimerization. Importantly, the EGF-induced and constitutive oncogenic potential of these EGFR mutants are inhibited by cetuximab or panitumumab in vivo and in vitro. Taken together, we propose that a subset of EGFR mutations can serve as genomic predictors for response to anti-EGFR antibodies and that metastatic CRC patients with such mutations may benefit from these drugs as part of the first-line therapy.

Keywords: EGFR mutation; cetuximab (Erbitux); colon cancer; epidermal growth factor receptor (EGFR); panitumumab; receptor dimerization; targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / enzymology
  • Adenocarcinoma / genetics
  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • Cetuximab / pharmacology*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / genetics
  • Dimerization
  • ErbB Receptors / genetics
  • ErbB Receptors / immunology
  • ErbB Receptors / metabolism
  • HT29 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Targeted Therapy
  • Mutation
  • NIH 3T3 Cells
  • Panitumumab / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Immunological
  • Panitumumab
  • EGFR protein, human
  • ErbB Receptors
  • Cetuximab